Patricia W. Slattum, Emily P. Peron, and Angela Massey Hill
KEY CONCEPTS
Alzheimer’s disease (AD) is the most common form of dementing illness, and the prevalence of AD increases with each decade of life.
The etiology of AD is unknown, and current pharmacotherapy neither cures nor arrests the pathophysiology.
Neuritic plaques and neurofibrillary tangles are the pathologic hallmarks of AD; however, the definitive cause of this disease is yet to be determined.
AD affects multiple areas of cognition and is characterized by a gradual onset with a slow, progressive decline.
A thorough physical examination (including neurologic examination), as well as laboratory and imaging studies, is required to rule out other disorders and diagnose AD before considering drug therapy.
Pharmacotherapy for AD focuses on impacting three domains: cognition, behavioral and psychiatric symptoms, and functional ability.
Nondrug therapy and social support for the patient and family are the primary treatment interventions for AD.
Cholinesterase inhibitors and memantine are used to treat cognitive symptoms of AD; other medications have been suggested to be beneficial because of their potential preventive or cognitive effects.
Appropriate management of vascular disease risk factors may reduce the risk for developing AD and may prevent the worsening of dementia in patients with AD.
A thorough behavioral assessment and plan with careful examination of environmental factors should be conducted before initiating drug therapy for behavioral symptoms.
“I now begin the journey that will lead me into the sunset of my life.”
Ronald Reagan
Alzheimer’s disease (AD), first characterized by Alois Alzheimer in 1907, is a gradually progressive dementia affecting cognition, behavior, and functional status. The exact pathophysiologic mechanisms underlying AD are not entirely known, and no cure exists.1 Although drugs may reduce AD symptoms for a time, the disease is eventually fatal.
AD profoundly affects the family as well as the patient. The need for supervision and assistance increases until the late stages of the disease, when AD patients become totally dependent on a caregiver for all of their basic needs. These are the all-too-common experiences of the millions of people in the United States who care for someone with AD. To address the growing AD crisis facing the United States, the first national strategic plan, the National Alzheimer’s Plan, was released in 2012 with the goals of coordinating efforts across the federal government to prevent and treat AD, increase public awareness, and improve the quality of care and support for patients and their caregivers.2
EPIDEMIOLOGY
AD is the most common cause of dementia, accounting for 50% to 60% of cases of late-life cognitive dysfunction. Its prevalence among dementia patients increases to 80% if AD lesions in conjunction with other pathologic brain lesions are considered.3–5 Table 38-1 lists the most common types of dementia. Dementia can result from multiple etiologies. This chapter focuses exclusively on dementia of the Alzheimer’s type. However, the reader is encouraged to use the nonpharmacologic approaches and management of behavioral problems outlined in this chapter as a general treatment approach for other types of dementia that may share similar features with AD.
TABLE 38-1 Common Types of Dementia in Late Life
Approximately 5.4 million Americans have AD.4,5 By the year 2050, one in five people will be older than age 65 years, and the number of AD patients is projected to be 13.2 million (Fig. 38-1). Most cases present in persons older than age 65 years, but approximately 4% of cases occur in persons younger than age 65 years. Onset can be as early as age 30 years, resulting in the arbitrary age classifications of younger-onset (age less than 65 years) and late-onset (age 65 years and older).4
FIGURE 38-1 Our aging population. The percentage of U.S. population older than age 65 years and the percentage with AD projected from years 2000 to 2050. (Estimates based on data from references 1 and 134.)
Increasing age is the greatest risk factor for AD, but AD is not a normal part of aging. The prevalence of AD increases exponentially with age, affecting approximately 4% of people <65 years, 6% of individuals age 65 to 74 years, 44% of those age 75 to 84 years, and 46% of persons age 85 years and older.4 Factors determining age of onset and rate of progression remain largely undefined.
Survival following AD diagnosis is typically 4 to 8 years, but may be as long as 20 years. It is the fifth leading cause of death for those age 65 years and older in the United States. AD may not cause death directly. The most common cause of death in patients with AD is pneumonia, possibly resulting from swallowing difficulties and immobility in the terminal stage of the disease.4 Those diagnosed with AD spend, on average, more years in the most severe stage of the disease than any other stage, and much of this time is spent in a nursing home.4
Etiology and Genetics
The exact etiology of AD is unknown; however, several genetic and environmental factors have been explored as potential causes of AD. Dominantly inherited forms of AD account for less than 1% of cases.6,7 More than half of young-onset, dominantly inherited cases of AD can be attributed to alterations on chromosomes 1, 14, or 21. The majority and most aggressive young-onset cases are attributed to mutations of a gene located on chromosome 14, which produces a protein called presenilin 1.8 A structurally similar protein, presenilin 2, is produced by a gene on chromosome 1. Both presenilin 1 and presenilin 2 encode for membrane proteins that may be involved in amyloid precursor protein (APP) processing. Scientists have identified more than 160 mutations in presenilin genes, and these mutations appear to result in reduced activity of γ-secretase, an enzyme important in β-amyloid peptide (Aβ) formation.8 APP is encoded on chromosome 21. Only a small number of young-onset familial AD cases have been associated with mutations in the APP gene, resulting in overproduction of Aβ or an increase in the proportion of Aβending at residue 42.8
Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE) genotype.6–9 Thus far, the contribution of other candidate genes appears to be minor, although AD may be a heterogeneous disease resulting from complex interactions among multiple susceptibility genes and environmental factors. There are three major subtypes or alleles of APOE (e.g., *2, *3, and *4). Inheritance of the APOE*4 allele is believed to account for much of the genetic risk in late-onset AD. The mechanism through which APOE*4 confers an increased risk is unknown, although APOE*4 is associated with factors that may contribute to AD pathology, such as abnormalities in mitochondria, cytoskeletal dysfunction, and low glucose usage.5 The risk for AD is two- to threefold higher in individuals with one APOE*4 allele and 12-fold higher in individuals with two APOE*4 alleles compared to those with no APOE*4 alleles.9 Moreover, onset of symptoms occurs at a relatively younger age as compared with patients having zero or only one copy of APOE*4 in their genotype.9 The strength of association is not the same across all races however.1,4 The APOE*4 allele is not diagnostic or even essential for disease presence.
Genetic factors have been linked to both younger- and late-onset AD. Genetic explanatory factors continue to be investigated.6–8 Epigenetic modifications, particularly DNA methylation, have been reported in AD, and this is an emerging area of research that may help explain the pathologic complexity of AD and aging as a risk factor for the development of AD.10
Environmental and Other Factors
A number of environmental factors are associated with an increased risk of AD, including age, decreased reserve capacity of the brain (reduced brain size, low educational level, and reduced mental and physical activity in late life), head injury, Down’s syndrome, depression, mild cognitive impairment (MCI), and risk factors for vascular disease (hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease, smoking, elevated homocysteine, obesity, metabolic syndrome, and diabetes).4,5,11 Whether these vascular risk factors are true causal risk factors for AD contributing to AD pathology, or whether they result in cerebrovascular pathology that, in turn, contributes to the symptoms of AD, remains to be established.
The incidence of AD rises with increasing age and AD may develop in individuals over the course of decades,4 suggesting that AD is a disease most people are in the process of developing throughout adulthood. The debate about whether dementia is a distinct disease or part of aging remains unresolved. An in-depth discussion of the aging—AD controversy is not possible in this chapter; it is reviewed elsewhere.12–14
PATHOPHYSIOLOGY
The signature lesions in AD are amyloid plaques and neurofibrillary tangles (NFTs) located in the cortical areas and medial temporal lobe structures of the brain.3 Along with these lesions, degeneration of neurons and synapses, as well as cortical atrophy occurs. Plaques and NFTs may also be present in other diseases, even in normal aging, but at least in younger demographics there tends to be a higher burden of plaques and NFTs in AD-affected subjects than there is in age-matched controls. Several mechanisms have been proposed to explain changes in the brain that result in symptoms of AD, including misfolding of proteins (Aβ aggregation and deposition leading to the formation of plaques and hyperphosphorylation of tau protein leading to NFT development); synaptic failure and depletion of neurotrophin and neurotransmitters; and mitochondrial dysfunction (oxidative stress, impaired insulin signaling in the brain, vascular injury, inflammatory processes, loss of calcium regulation, and defects in cholesterol metabolism).3
Amyloid Cascade Hypothesis
Amyloid plaques are extracellular lesions found in the brain and cerebral vasculature. Plaques largely consist of Aβ. Aβ peptides consisting of 36 to 43 amino acids are produced via processing of a larger protein, APP. Aβ42 is less common than other Aβ peptides, but is prone to aggregation and plaque formation.3 The amyloid cascade hypothesis states that there is an imbalance between the production and clearance of Aβ peptides resulting in aggregation that causes accumulation of Aβ ultimately leading to AD.3 Studies on younger-onset AD and Down’s syndrome led to the formulation of the amyloid cascade hypothesis. Recent versions of the amyloid cascade hypothesis assume Aβthat is not sequestered in plaques actually drives the disease.3 Even so, the amyloid cascade hypothesis seems most applicable in cases of younger-onset, autosomal dominant AD. It is not clear whether it is reasonable to etiologically extrapolate to the late-onset form (which afflicts the vast majority of those affected). Whether individuals with late-onset AD also carry genetic variations that promote a primary Aβ amyloidosis remains to be shown. If this turns out not to be the case, the possibility that amyloidosis in late-onset AD is secondary to a more upstream event will require consideration. Before this conceptual conundrum is laid to rest, however, the amyloid cascade hypothesis will likely undergo a therapy-based practical test. If treatments that efficiently reduce Aβ production or remove brain Aβ fail to arrest disease progression, it would argue amyloidosis is not the primary pathology in most of those with AD.
Neurofibrillary Tangles
As Aβ was being identified in plaques, other researchers showed that NFTs are commonly found in the cells of the hippocampus and cerebral cortex in persons with AD and are composed of abnormally hyperphosphorylated tau protein. Tau protein provides structural support to microtubules, the cell’s transportation and skeletal support system.3 When tau filaments undergo abnormal phosphorylation at a specific site, they cannot bind effectively to microtubules, and the microtubules collapse. Without an intact system of microtubules, the cell cannot function properly and eventually dies. The density of the NFTs correlates with the severity of the dementia.3 NFTs are found in other dementing illnesses besides AD, and may represent a common method by which various inciting factors culminate in cell death.3
Inflammatory Mediators
Inflammatory or immunologic paradigms are often viewed as a corollary of the amyloid cascade hypothesis. Certainly, brain amyloid deposition associates with local inflammatory and immunologic alterations. This led some to propose that inflammation is relevant to AD neurodegeneration.3 Inflammatory/immunologic hypotheses argue that although Aβ may have direct neurotoxicity, at least some of its toxicity might actually be an indirect consequence of an Aβ protofibril-induced microglia activation and astrocyte recruitment. This inflammatory response may represent an attempt to clear amyloid deposition. However, it is also associated with release of cytokines, nitric oxide, and other radical species, and complement factors that can both injure neurons and promote ongoing inflammation.3 Indeed, levels of multiple cytokines and chemokines are elevated in AD brains, and certain proinflammatory gene polymorphisms are reported to be associated with AD.3
Consistent with these molecular observations are epidemiologic data suggesting that exposure to nonsteroidal antiinflammatory drugs (NSAIDs) may reduce AD risk.15,16 However, multiple prospective short duration trials of NSAIDs in AD prevention and of NSAIDs as AD treatment have been disappointing.3,17
The Cholinergic Hypothesis
Multiple neuronal pathways are destroyed in AD. Neuronal damage can be seen in conjunction with plaque structures.3 Widespread cell dysfunction or degeneration results in a variety of neurotransmitter deficits, with cholinergic abnormalities being the most prominent.3 Loss of cholinergic activity correlates with AD severity. In the late stage of AD, the number of cholinergic neurons is reduced, and there is loss of nicotinic receptors in the hippocampus and cortex. Presynaptic nicotinic receptors control the release of acetylcholine, as well as other neurotransmitters important for memory and mood, including glutamate, serotonin, and norepinephrine.3
The discovery of vast cholinergic cell loss led to the development of a cholinergic hypothesis of the pathophysiology of AD. The cholinergic hypothesis targeted cholinergic cell loss as the source of memory and cognitive impairment in AD. Consequently, it was presumed that increasing cholinergic function would improve symptoms of memory loss. This approach is flawed because cholinergic cell loss appears to be a secondary consequence of Alzheimer’s pathology, not the disease-producing event, and cholinergic neurons are only one of many neuronal pathways destroyed in AD. Simple addition of acetylcholine cannot compensate for the loss of neurons, receptors, and other neurotransmitters lost during the course of the illness. Thus the goal is to minimize or improve symptoms through augmentation of neurotransmission at remaining synapses.
Other Neurotransmitter Abnormalities
Although the cholinergic system has received particular attention in AD pharmaceutical research, deficits also exist in other neuronal pathways. For example, serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus are lost, while monoamine oxidase type B activity is increased. Monoamine oxidase type B is found predominantly in the brain and in platelets, and is responsible for metabolizing dopamine. In addition, abnormalities appear in glutamate pathways of the cortex and limbic structures, where a loss of neurons leads to a focus on excitotoxicity models as possible contributing factors to AD pathology.
Glutamate is the major excitatory neurotransmitter in the cortex and hippocampus. Many neuronal pathways essential to learning and memory use glutamate as a neurotransmitter, including the pyramidal neurons (a layer of neurons with long axons carrying information out of the cortex), hippocampus, and entorhinal cortex. Glutamate and other excitatory amino acid neurotransmitters have been implicated as potential neurotoxins in AD.18 Dysregulated glutamate activity is thought to be one of the primary mediators of neuronal injury after stroke or acute brain injury. Although intimately involved in cell injury, the role of excitatory amino acids in AD is as yet unclear; however, blockade of N-methyl-D-aspartate (NMDA) receptors decreases activity of glutamate in the synapse and may hypothetically lessen the degree of cellular injury in AD.
Brain Vascular Disease and High Cholesterol
There is growing evidence of a causal association between cardiovascular disease and its risk factors and the incidence of AD. Cardiovascular risk factors that are also risk factors for dementia include hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and diabetes.19 Brain vascular disease may augment the cognitive impairment observed for a given amount of AD pathology in the brain. Dysfunctional blood vessels may impair nutrient delivery to neurons and reduce clearance of Aβ from the brain.3 Vascular disease may accelerate amyloid deposition and increase amyloid toxicity to neurons.3 Midlife diastolic hypertension is adversely associated with AD, while late-life hypertension may show an inverse association with AD.20 Diabetes may increase the risk of dementia through factors related to “metabolic syndrome” (dyslipidemia and hypertension), effects of potentially toxic glucose metabolites on the brain and vasculature, and through insulin itself.19Disturbances in insulin-signaling pathways, both in the periphery and the brain, have been linked to AD. Insulin may also regulate the metabolism of Aβ and tau protein.3
Research has found multiple links between cholesterol and AD. APOE is synthesized in the liver, central nervous system, and cerebrospinal fluid (CSF) and is responsible for transporting cholesterol in the blood through the brain. It is carried by low-density lipoprotein into neurons and binds to NFTs. APOE*4 is associated with increasing deposition of Aβ and is thought to act as an accelerating modulator in vascular dementia. Elevated cholesterol levels in brain neurons may alter membrane functioning and result in the cascade leading to plaque formation and AD.
Other Mechanisms
Other hypotheses proposed to explain AD pathogenesis include oxidative stress, mitochondrial dysfunction, and loss of estrogen. Each of these mechanisms may contribute to AD pathogenesis, but the extent of the contribution is uncertain. There is a growing body of evidence of a role for oxidative stress and the accumulation of free radicals in the brain of AD patients.3 Some epidemiologic studies suggest vitamin E, and possibly the combination of vitamin E and vitamin C, may reduce AD risk while others do not.3 Mitochondrial dysfunction may result in disruption of energy metabolism in the neuron.3,21,22The role of estrogen in cognitive aging and dementia continues to be an active area of investigation. Despite convincing evidence that estrogens affect the brain in ways that would be expected to improve cognitive aging and reduce the risk of AD, the results of clinical studies have been largely disappointing.21A single common mechanism for producing AD does not exist. Regardless of the source, however, the features remain the same: degeneration of neurons in higher brain areas; accumulation of NFTs and amyloid plaques; profound destruction of cholinergic pathways; and an insidious dementia, slowly progressive until death.
CLINICAL PRESENTATION OF ALZHEIMER’S DISEASE
The onset of AD is almost imperceptible, without abrupt changes in cognition or function. Deficits occur progressively over time, affecting multiple areas of cognition.4,22 For treatment and assessment purposes, it is helpful to divide AD symptoms into two basic categories: cognitive symptoms and noncognitive (behavioral) symptoms. Cognitive symptoms are present throughout the illness, whereas behavioral symptoms are less predictable. Table 38-2summarizes the stages of AD.
TABLE 38-2 Stages of Alzheimer’s Disease
Diagnosis
A family member often first brings memory complaints to the attention of a primary care clinician. Up to 50% of patients who meet criteria for dementia are not given a diagnosis in the primary care setting, leading some to believe that an appropriate screening tool may be helpful in aiding diagnosis and leading to earlier treatment.23,24 Despite the phenomenon of underdiagnosis, the United States Preventative Services Task Force concluded that there are insufficient data to recommend for or against cognitive screening for AD, because it could not be determined if the benefits outweigh the risks.23 Screening is being promoted as part of the Medicare Annual Wellness Visit by the Alzheimer’s Association (AA).25
Until recently the only way to confirm a clinical diagnosis of AD was through direct examination of brain tissue at autopsy or biopsy. Several criteria have been used in clinical practice and research for the detection and diagnosis of dementia, including the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria,26 the Agency for Healthcare Research and Quality (AHRQ) Guidelines,27 the American Academy of Neurology Guidelines,28 the National Institute of Neurological Disorders and Stroke (NINDS) criteria,29 and the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS), and the Alzheimer’s Disease and Related Disorders Association (ADRDA) Criteria.30 In 2011, revisions to the NINCDS and ADRDA Criteria for the clinical diagnosis of AD were recommended by the National Institute on Aging (NIA) and the AA25,31 DSM-5 provides criteria for diagnosis of minor and major neurocognitive disorders, with specific criteria for neurocognitive disorders due to AD.32 The new NIA-AA criteria view AD as a spectrum beginning with a preclinical phase progressing to increasingly severe clinical stages of AD. Three workgroups formulated diagnostic criteria for the dementia phase,33 the symptomatic, predementia phase (MCI),34 and the asymptomatic, preclinical phase of AD.35 At this time, AD is still primarily a clinical diagnosis, but this is expected to change in coming years as brain imaging, CSF, and other AD biomarkers are validated and available for routine clinical use. The patient’s examination should suggest that cognitive decline from a previously higher baseline has occurred. The history should corroborate this, and further indicate that cognitive decline has reached the point where changes in social or occupational functioning are present. It is possible to administer a sophisticated exam that defines cognitive domain strengths and weaknesses and enables a neuroanatomic localization of the observed deficits. When approached in this way, the exam can indicate a pattern of cognitive decline that is consistent with AD, and assist with rendering a diagnosis that is as much a diagnosis of inclusion as it is of exclusion.
CLINICAL PRESENTATION Alzheimer’s Disease
General
• The patient may have vague memory complaints initially, or the patient’s significant other may report that the patient is “forgetful.” Cognitive decline is gradual over the course of illness. Behavioral disturbances may be present in moderate stages. Loss of daily function is common in advanced stages
Symptoms
Cognitive
• Memory loss (poor recall and losing items)
• Aphasia (circumlocution and anomia)
• Apraxia
• Agnosia
• Disorientation (impaired perception of time and unable to recognize familiar people)
• Impaired executive function
Noncognitive
• Depression, psychotic symptoms (hallucinations and delusions)
• Behavioral disturbances (physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness)
Functional
• Inability to care for self (dressing, bathing, toileting, and eating)
Laboratory Tests
• Rule out vitamin B12 and folate deficiency
• Rule out hypothyroidism with thyroid function tests
• Blood cell counts, serum electrolytes, and liver function tests
Other Diagnostic Tests
• CT or MRI scans may aid diagnosis
Objectively defining social or occupational dysfunction can prove tricky in the older patient who may be retired, and who may also lead a socially restricted lifestyle for reasons of frailty. For such patients, the minimal requirement is to establish a change in activities of daily living. Early on, this usually involves a change in instrumental activities of daily living (handling finances, organizing medications) rather than basic activities of daily living (hygiene, dressing). Some AD subspecialists use a detailed, standardized, semistructured interview of a nonpatient informant as the most critical piece of the diagnostic evaluation.36
For patients who meet criteria for dementia (whether the underlying cause is ultimately felt to be AD or not), current recommendations from the American Academy of Neurology include a neuroimaging study (computed tomography or magnetic resonance imaging), as well as a serologic evaluation that includes blood cell counts, serum electrolytes, liver function tests, a test of thyroid function, and a vitamin B12 level.28 When circumstances suggest AD is not the leading entity on the differential diagnosis, other neurologic tests such as CSF analysis or electroencephalogram can occasionally be justified. Neuropsychological testing is also optional, but can prove quite useful for the diagnosis of AD by helping to establish a neuroanatomical localization for the patient’s cognitive deficits.
Almost any medication can contribute to cognitive impairment in vulnerable individuals, but certain classes of medication are more commonly implicated. Benzodiazepines and other sedative hypnotics, anticholinergics, opioid analgesics, antipsychotics, and anticonvulsants have been associated with cognitive impairment.37,38 NSAIDs, histamine H2-receptor antagonists, digoxin, amiodarone, antihypertensives, and corticosteroids have been implicated in cases of delirium.37 Because medications are a reversible cause of cognitive symptoms, medication review and management are essential.
Efforts to define the role of other AD diagnostic tests are ongoing. Positron emission tomography scanning may reveal a pattern of hypometabolism typical of AD, but by itself the diagnostic accuracy of positron emission tomography scanning still lags behind that of the clinical examination and history.39 APOE genotyping by itself is also insufficient to make or break a diagnosis of AD, but demonstrating an APOE*4 allele in a suspected patient increases the specificity of the diagnosis and can help predict which patients with MCI are most likely to progress to a diagnosis of AD over the next several years.40Unless the patient developed dementia prior to age 60 years and also had a parent that developed AD before age 60 years, presenilin 1, presenilin 2, or APP genotyping is usually not indicated.
Mild Cognitive Impairment
It has long been recognized that aging individuals experience changes in cognitive function. MCI constitutes a syndromic designation that categorizes patients with cognitive complaints insufficient to warrant a diagnosis of dementia. The NIA-AA diagnostic criteria specifically address the diagnosis of MCI.34 Persons diagnosed with MCI carry a 10% to 15% chance per year of progressing to an AD diagnosis.41What clinicians are likely seeing in most people with MCI is the initial manifestation of a progressive degenerative dementia that will eventually meet AD diagnostic criteria.34,41 However, it is important to note that not everyone meeting MCI criteria will have AD. As the MCI designation is increasingly applied, MCI criteria continue to evolve.34,41
TREATMENT
Desired Outcomes
The primary goal of treatment in AD is to symptomatically treat cognitive difficulties and preserve patient function as long as possible. Secondary goals include treating the psychiatric and behavioral sequelae. Current AD treatments have not been shown to prolong life, cure AD, or halt or reverse the pathophysiologic processes of the disorder.36
General Treatment Approach
Clinical trials have consistently demonstrated modest benefits of early and continuous treatment with cholinesterase inhibitors.42 Memantine added in moderate to severe disease may also provide benefit. Following this approach allows for maximal maintenance of cognition and activities of daily living. A symptomatic approach is used to treat behavioral symptoms as they arise.
Provision of education to the patient and family at the time of diagnosis, including discussion of the course of illness, realistic expectations of treatment, and the importance of legal and financial planning, are essential to appropriate treatment.
Nonpharmacologic Therapy
AD has a profound effect on both the patient and family, so appropriate treatment is needed. Nonmedication interventions are the current primary interventions for management of AD, and medications should be used in the context of multimodal interventions. Behavioral and psychiatric symptoms are among the most challenging and distressing symptoms of the disease and may be the determining factor in a family’s decision to seek institutional care. Symptoms such as sleep disturbances, wandering, urinary incontinence, agitation, and aggression in patients with dementia are best managed using behavioral interventions rather than medications whenever possible.42–44
Upon initial diagnosis, the patient and caregiver should be educated on the course of illness, prognosis, available treatments, legal decisions, and quality-of-life issues. Caregiving strategies, including stress-management techniques and support group options, should also be discussed. Caregiver education and support programs have been shown to improve caregiver skill, knowledge, confidence, and quality of life, and, in some cases, delay time to nursing home placement.45,46 Table 38-3 lists basic principles of care for the AD patient. The general approach to nonmedication strategies for behavioral symptoms is to identify the symptom, identify causative factors, and adapt the caregiving environment to remedy the situation.4 Environmental triggers may include noise, glare, an insecure space, and too much background distraction, including television. Personal discomfort may also trigger behaviors, so it is important to monitor for pain, hunger, thirst, constipation, full bladder, fatigue, infections, skin irritation, comfortable temperature, fears, and frustrations.4 Medical comorbidity is a major source of functional and cognitive impairment in patients with AD, so general health maintenance is warranted.4 Interventions should redirect the patient’s attention rather than be confrontational and should specifically address known triggers. Creating a calm environment and removing stressors and triggers is key. Other nonpharmacological approaches include exercise, light therapy, music therapy, reminiscence therapy, aroma therapy, relaxation techniques, validation therapy, massage and touch therapy, and multisensory stimulation.47Caregivers should be referred to support services, such as the AA, for assistance in developing nonpharmacologic strategies for managing difficult behaviors.
TABLE 38-3 Basic Principles of Care for the Alzheimer’s Patient
The caregiver must be prepared to face the changes in life that will occur, and acceptance of this does not come easily. Denial on the part of the patient and rationalization on the part of the family are common. The clinician should encourage the family to address legal and financial matters and designate a durable power of attorney for execution of financial and medical decisions once the patient is incompetent. The caregiver will need to address issues such as respite services to provide time for rest, relaxation, and conduct of personal business. Eventually, the caregiver will need to face critical and difficult questions with respect to institutionalization. Local resources, such as the AA, can provide detailed information regarding support services. Table 38-4 lists this and other referral sources for caregivers.
TABLE 38-4 Resources for Caregivers of Persons with Alzheimer’s Disease
Education, communication, and planning are key nonpharmacologic components of caring for a patient with AD. Preparation in the early stages of illness may lessen some of the caregiver stress as the illness progresses.
Pharmacologic Therapy
Pharmacotherapy for Cognitive Symptoms
Table 38-5 presents a treatment algorithm for managing cognitive symptoms in AD. Cholinesterase inhibitors and NMDA-receptor antagonists are indicated for treatment of AD. The latest treatment guidelines recommend the use of cholinesterase inhibitors for AD, with no preference for a specific agent.48–50 Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD, while donepezil is also indicated in severe disease. Memantine is indicated for moderate to severe AD; current evidence does not support its use in earlier stages of the disease.51 Additional benefit may be achieved when memantine is added to cholinesterase inhibitor therapy in moderate to severe AD.52 There is no evidence supporting combination therapy of more than one cholinesterase inhibitor. No head-to-head trials comparing memantine monotherapy to cholinesterase inhibitor therapy have been conducted to date.
TABLE 38-5 Treatment Options for Cognitive Symptoms in Alzheimer’s Disease
Disagreement exists about how best to determine effectiveness of treatments for AD. Selection of qualitative versus quantitative assessment may bias a clinician’s impression of response. Subtle changes are often detected only by psychometric testing. Because no standard has been suggested to define the effectiveness of medications for AD, great variation exists between clinicians, and the duration of treatment ranges from months to years. Realistic expectations for treatment success may include slowed decline in behavioral, functional, and cognitive abilities and delayed long-term care placement.53
Unfortunately, clinical trials have failed to provide answers to key questions in treating AD patients. Information from clinical trials is insufficient to know if a cholinesterase inhibitor dose–response relationship exists, or if additional cognitive improvement may be gained by increasing to the maximum tolerated dose, rather than continuing with the usual recommended daily dosage. Guidance in extrapolating data related to changes in cognition is needed, so that a reasonable duration of clinical treatment with cholinesterase inhibitors and NMDA-antagonists can be determined. One concern is that those who respond to treatment may lose the benefits of that treatment once the medication is stopped.54,55 Moreover, gaps in treatment have been linked with worse outcomes in open-label trials;56,57however, in a more recent large observational study there was no increased risk of institutionalization or death associated with gaps in cholinesterase inhibitor therapy.58 Regardless, dosing regimens should be simplified and patient/caregiver preferences considered in an effort to improve adherence and persistence.
In natural disease progression studies, scores on the Alzheimer’s Disease Assessment Scale—Cognition (ADAS-cog) have been shown to worsen (increase) by an average of less than or equal to five points over 1 year in mild dementia and 7 to 11 points annually in moderate dementia. Based on these findings, the general consensus is that a four-point change in the ADAS-cog represents a clinically significant change.42 Therefore, if a pharmacotherapeutic agent decreases the ADAS-cog score by four points, one could think of this as having delayed progression of disease symptoms by 6 months. The usefulness of the ADAS-cog in clinical practice is limited because of the time required for administration; it is much more practical to assess changes in disease severity using the Mini-Mental Status Examination (MMSE). An untreated patient has an average decline of two to four points in MMSE score per year. Successful treatment would reflect a decline of less than two points a year. It is reasonable to change to a different cholinesterase inhibitor if the decline in MMSE score is greater than two to four points after 1 year with the initial agent.59
Cholinesterase Inhibitors In the early 1980s, researchers began to examine means to enhance cholinergic activity in patients with AD by inhibiting the hydrolysis of acetylcholine through reversible inhibition of cholinesterase. Tacrine was the first such drug to be examined in a systematic fashion. However, tacrine was fraught with significant side effects, including hepatotoxicity, which severely limited its usefulness. Tacrine is no longer available in the US market, having been replaced by safer, more tolerable cholinesterase inhibitors. The newer cholinesterase inhibitors donepezil, rivastigmine, and galantamine show similar symptomatic improvement in cognitive, global, and functional outcomes in patients with mild to moderate AD, and duration of benefit varies from 3 to 12 months.60–62
The mechanism of action differs slightly between drugs in this class.59 Donepezil specifically and reversibly inhibits acetylcholinesterase. Rivastigmine inhibits both butyrylcholinesterase and acetylcholinesterase. Galantamine is a selective, competitive, reversible acetylcholinesterase inhibitor and also enhances the action of acetylcholine on nicotinic receptors. The clinical relevance of these differences is unknown.
Choice of cholinesterase inhibitor therapy for an individual patient is based on ease of use, patient preference, cost, and safety issues, such as potential for drug interactions.48,49 Pharmacokinetic properties should also be considered, as rivastigmine and galantamine have short half-lives (1.5 and 7 hours, respectively) as compared to donepezil (70 hours). As such, if rivastigmine or galantamine treatment is interrupted for several days or longer, the patient should be restarted at the lowest dose and titrated to the current dose. This is true for all formulations of these drugs, including the Exelon® patch.63–66 Dosing strategies for cholinesterase inhibitors and memantine are summarized in Table 38-6.
TABLE 38-6 Dosing of Drugs Used for Cognitive Symptoms
Adverse drug reactions and corresponding monitoring parameters are described in Table 38-7. Cholinesterase inhibitors have similar adverse event profiles, and this class of drugs is generally well-tolerated. The most frequent adverse events associated with these agents are mild to moderate GI symptoms (e.g., nausea, vomiting, and diarrhea).52 Gradual dose titration over several months can improve tolerability.50Alternatives to the immediate-release tablet/capsule dosage form are available for patients who have complex dosing regimens, tolerability issues, or difficulty swallowing, though cost may be prohibitive until they are generically available. Patients and caregivers should be cautioned against abrupt discontinuation of cholinesterase inhibitor therapy, as this can lead to worsening cognition and behavior in some patients.67,68 Concurrent use of anticholinergic medications with cholinesterase inhibitors should also be avoided.69 Depending on individual patient response, tolerability, and preference, switching to an alternate dosage form of cholinesterase inhibitor agent may be necessary during the course of AD treatment. Manufacturer recommendations for switching between dosage forms of the same drug are specified in the prescribing information, but the optimal procedure for switching between agents remains uncertain. Length of the washout period when switching from one cholinesterase to another may vary based on drug pharmacokinetics; however, 1 week is generally sufficient.70
TABLE 38-7 Monitoring Drug Therapy for Cognitive Symptoms
Antiglutamatergic Therapy Memantine is the only NMDA-antagonist currently available. At concentrations achieved at least under in vitro conditions, memantine blocks glutamatergic neurotransmission by antagonizing NMDA receptors. Glutamate is an excitatory neurotransmitter in the brain implicated in long-term potentiation, a neuronal mechanism important for learning and memory.71 Blocking NMDA receptors can mitigate excitotoxic neurotoxicity and provide neuroprotection. There is currently no clinical evidence to indicate memantine confers neuroprotection in AD.42,51,71
Memantine is currently indicated for use in moderate to severe AD. Its use has been studied in patients with moderate and severe AD as monotherapy and in combination with donepezil with favorable results on cognition and function.51 Studies of memantine alone and in combination with cholinesterase inhibitors in mild AD performed to date have provided insufficient evidence to support an indication for mild AD.42
In its tablet or oral solution form, memantine should be initiated at 5 mg once a day and titrated weekly in 5 mg intervals to the target maintenance dose of 10 mg twice daily. The extended-release capsule form of memantine is to be initiated at 7 mg daily and titrated up to a maximum of 28 mg daily. Dose titration is achieved in 7 mg intervals with at least 1 week between dose adjustments. Dosing of 5 mg twice daily (tablet, oral solution) or 14 mg daily (extended-release capsule) is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min [0.08 to 0.49 mL/s]).
Overall, memantine has been well-tolerated in clinical trials. The most common adverse events include headache, constipation, confusion, and dizziness.72,73 Memantine has 100% bioavailability regardless of administration with or without food. Protein binding is relatively low (45%). Memantine is not metabolized by the liver and does not inhibit cytochrome P450 activity. It is primarily excreted unchanged in the urine, and the half-life of memantine ranges from 60 to 80 hours.72,73
Role of Combination Therapy Combination therapy with memantine added to cholinesterase inhibitor therapy is generally prescribed for patients with moderate to severe AD. The rationale for this add-on therapy is that the drug classes have different mechanisms of action. In an observational study, memantine plus a cholinesterase inhibitor was compared to cholinesterase inhibitor monotherapy and to no treatment with either. Combination therapy slowed cognitive and functional decline to a statistically significant degree compared to the other groups; this was a 4-year sustained effect that appeared to increase over time.74 A randomized controlled trial (RCT) randomized patients with moderate to severe AD already receiving stable donepezil treatment to either memantine or placebo. At the end of this 6-month trial, patients randomized to memantine (combination therapy) had significantly better outcomes in measures of cognition, function, behavior, and global status than those randomized to placebo (donepezil monotherapy). The group randomized to receive memantine also had a lower rate of discontinuation due to adverse events versus placebo.75 Based on data from this study and others, memantine may have a role in mitigating GI adverse events associated with cholinesterase inhibitors.42,75
Effect of Current Treatments on Neurodegenerative Processes AD is a progressive disorder. Affected individuals typically experience some degree of cognitive decline and histologic change years (if not decades) before a diagnosis is made. Therefore, the ideal treatment will be one that not only reverses symptoms by enhancing cognitive function (a symptomatic treatment), but also arrests the neurodegeneration-relevant molecular processes that underlie cognitive decline (a disease-modifying treatment).
Clinical trials for AD prompt consideration of whether positive outcomes suggest either a symptomatic or disease-modifying effect. Any rapid performance improvement on cognitive ability, activities of daily living, or behavioral end points is indicative of a symptomatic effect. All cholinesterase inhibitor agents and memantine demonstrate this pattern. On the other hand, arrest of decline or a sustained reduction in the slope of decline would argue the presence of a disease-modifying effect. It has not been possible to unequivocally demonstrate this in trials of the currently approved treatments. Long-duration, double-blind, placebo-controlled trials to evaluate whether cholinesterase inhibitors, with or without memantine, have disease-modifying effects are difficult to perform, because doing so would require continuing a placebo arm over an extended period, well beyond demonstration of symptomatic benefit. Also, subject attrition over an extended study would complicate both intent-to-treat and observed cases analyses.
With the currently approved AD drug treatments, pivotal placebo-controlled trials were followed by open-label extension studies. Published studies have lasted as long as 5 years, and as part of these studies, decline in the treatment group was compared with “projected” placebo groups based on the placebo groups followed during the 6-month randomized phase of the efficacy study, as well as natural history cohorts from the precholinesterase inhibitor therapy era. Although analyses of this sort conclude that, for up to at least 5 years, persons receiving treatment exceed their projected nontreatment cognitive performance, no convincing evidence of a disease-modifying effect emerges.76–80
Clinical Controversy…
In light of the irreversible nature of AD, the question of whether to intervene at the time of AD diagnosis or earlier (when patients are asymptomatic or exhibit symptoms of MCI) remains controversial. Some studies suggest cognitive benefits in patients with MCI treated with cholinesterase inhibitors. However, cholinesterase inhibitors have not been shown to prevent conversion from normal cognition or MCI to AD. Despite inconclusive evidence for early intervention, cholinesterase inhibitors are commonly prescribed off-label prior to formal diagnosis of AD.81–83
Management of Brain Vascular Health
Guidelines for the care of patients with AD support the management of vascular brain disease and its associated risk factors as part of the treatment of AD.84 There is a growing body of evidence that brain vascular disease may play a role in the progression of dementia. For a given level of Alzheimer’s pathology, vascular disease in the brain may add to the degree of cognitive impairment.84 Management of brain vascular disease includes monitoring blood pressure, glucose, cholesterol, and homocysteine and initiation of appropriate interventions.84 Guidelines recommend low-dose aspirin therapy in patients with AD with significant brain vascular disease.84 Elevated homocysteine levels correlate with decreased performance on cognitive tests, but there remains insufficient evidence of a benefit of B vitamin supplementation (B6, B12, and folic acid) on cognitive function in patients with AD.1 The Alzheimer’s Association’s Maintain Your Brain campaign recommends staying physically, mentally, and socially active; adopting a low-fat, low-cholesterol diet rich in dark vegetables and fruit; and managing body weight, blood pressure, cholesterol, and blood sugar to reduce the risk of heart disease, stroke, and diabetes.4 Appropriate management of vascular disease risk factors may reduce the risk for developing AD,85 although currently insufficient evidence exists to draw definitive conclusions on the association between risk factor modification and risk of AD.11
Other Potential Treatment Approaches
Estrogen Estrogen replacement has been studied extensively for the treatment and prevention for AD. Most, but not all, retrospective epidemiologic studies show a lower incidence of AD in women who took estrogen replacement therapy postmenopausally. Prospective clinical trials have not supported the use of estrogen as a treatment for cognitive decline and longer trials tend to suggest harm. Overall, the evidence does not support the use of estrogen to treat or prevent dementia.49,86
Antiinflammatory Agents Retrospective epidemiologic studies suggest a protective effect against AD in patients who have taken NSAIDs. The benefits of antiinflammatory agents have been less compelling in prospective clinical studies. NSAIDs have had no cognitive benefit in AD patients or else benefits so minimal the risk of harm exceeds the potential benefit.17 Because there is a lack of compelling data and also a significant incidence of adverse effects, particularly gastritis and the possibility of GI bleeds, NSAIDs and prednisone are not recommended for general use in the treatment or prevention of AD.17
Lipid-Lowering Agents An AD protective effect has been postulated for lipid-lowering agents, particularly the 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors. Longitudinal epidemiologic studies suggest an association between elevated midlife total cholesterol levels and AD.19 Increased risk of dementia does not appear to be associated with hypercholesterolemia in late life however.19 Other studies note that the incidence of AD is lower in patients who have taken either a statin or another lipid-lowering agent, but not in patients who were taking other cardiovascular medications.19 It is important to note that not all epidemiologic studies suggest an association between cholesterol and AD.19
RCTs of statin therapy given in late life to patients at risk for vascular disease indicate that statins do not prevent AD.87 Several RCTs of statins for the treatment of mild to moderate AD have been completed or are ongoing. Thus far, these trials have not demonstrated a significant benefit of statin therapy, but results of ongoing trials should help to clarify the role of statins in the treatment of AD.88 Interestingly, cognitive impairment has been recognized as a rare adverse event associated with statin therapy. The extent of cognitive impairment may depend on the lipid solubility of the drug, regulating the amount of drug that is able to cross the blood–brain barrier. As simvastatin and lovastatin have the highest lipophilicity, they may be the most likely candidates to cause memory impairment.89 More research is needed to understand the complex relationship between cholesterol, statin therapy, and cognitive functioning. For now these agents should be reserved for patients who have other indications for their use.84
Dietary Supplements
Dietary supplements are widely used for the prevention and treatment of AD and available evidence has been recently reviewed.90–93 A detailed discussion of the many nutraceuticals, herbal products, and medical foods that have been promoted for the prevention and treatment of AD is beyond the scope of this chapter. The more commonly used dietary supplements are described here.
Vitamin E Based on pathophysiologic theories involving oxidative stress and the accumulation of free radicals in AD, significant interest has evolved regarding the use of antioxidants in the treatment of AD. Vitamin E was frequently recommended as adjunctive treatment for AD patients based on data from a clinical trial evaluating the time to critical end points (e.g., death, institutionalization, loss of ability to perform activities of daily living, or severe dementia) in patients treated with vitamin E, selegiline, the combination, or placebo.94 Although vitamin E and selegiline were superior to placebo, this study has been criticized because of differences in baseline cognitive severity, calling the validity of the results into question. Side effects observed with vitamin E administration include impaired hemostasis, fatigue, nausea, diarrhea, abdominal pain, and falls.94 A meta-analysis found that high-dose vitamin E increases mortality in supplemented subjects.95 In addition, vitamin E had no benefit in patients with MCI in the progression to AD.83 In light of these findings, vitamin E supplementation is no longer recommended for the treatment of AD. Vitamin E remains under investigation for the prevention of AD.
Ginkgo biloba G. biloba for the prevention and treatment of AD has been extensively studied. Proposed mechanisms for Ginkgo’s use in AD include its potential to increase blood flow, decrease blood viscosity, antagonize platelet-activating factor receptors, increase anoxia tolerance, inhibit monoamine oxidase, and serve as an antioxidant. Active ingredients in G. biloba include flavonoids, the Ginkgo flavone glycosides and bioflavonoids. Most studies reporting benefit in patients with AD have studied a standardized extract, EGb 761, in doses of 120 mg per day for at least 4 to 6 weeks. The clinical significance of the modest benefits detected is unclear and direct comparisons to cholinesterase inhibitors or memantine are lacking. Those advocating the use of Ginkgo for AD suggest doses of 120 to 240 mg of the standard leaf extract twice per day be used, and note 12 weeks of consistent dosing may be needed to observe an effect.96 However, a large trial of G. biloba in which the 120 mg twice a day dose was studied did not reduce either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or MCI.97 Another recent large trial found that the long-term use of G. biloba extract did not reduce the risk of progression to AD among older adults suffering from memory complaints compared with placebo.98 Side effects reported from EGb 761 studies were typically mild, including nausea, vomiting, diarrhea, headaches, dizziness, palpitations, restlessness, and weakness. Because EGb also has a potent antiplatelet effect, it should be avoided by individuals taking anticoagulant or antiplatelet therapies, and should be used cautiously in patients taking NSAIDs.96,99 Current practice guidelines do not recommend Ginkgo for the prevention or treatment of AD.84
Huperzine A It is an alkaloid isolated from the Chinese club moss, Huperzia serrata. It reversibly inhibits acetylcholinesterase and is administered orally in doses of 50 to 200 mcg two to four times daily. Clinical studies suggest huperzine A may have efficacy in the symptomatic treatment of AD, but more studies are needed to determine its place in therapy. In a medium-sized, randomized, double-blind, placebo-controlled, multicenter study in patients with mild to moderate AD performed in China, treatment with huperzine A at doses of 400 mcg/day for 12 weeks resulted in improvement in cognition by an average of 4.6 points assessed by ADAS-cog (P = 0.000), 2.7 points on the MMSE, and 1.5 points on the Alzheimer’s Disease Assessment Scale—noncognition (P = 0.008).100 Replication of these study results are still pending. The current consensus is that huperzine A has not been adequately studied for use in AD, its consistency in commercially available products remains a concern, and potential side effects could be significant, especially in those taking cholinesterase inhibitors.96,101
Polyphenols Several epidemiological studies have demonstrated that moderate ingestion of wine, but not distilled spirits, is associated with a lower incidence of AD.91 One of the components of red wine, resveratrol, has been the focus of research related to dementia. Resveratrol, a phenolic compound with antioxidant properties, is found commonly in foods such as grapes, peanuts, chocolate, blueberries, and red wine. Resveratrol’s proposed benefits in AD are to prevent reactive oxygen species-induced Aβ production and apoptosis-mediated neurodegeneration.91 Resveratrol 500 mg daily for 13 weeks followed by 1,000 mg daily for 39 weeks is currently under evaluation for the treatment of mild to moderate AD in a randomized, double-blind, placebo-controlled study.102
The polyphenol curcumin (turmeric) is a spice used in Indian curry that has antioxidant and antiinflammatory properties and has been proposed as one explanation for the lower incidence of AD in India compared to the United States.89 Curcumin may prevent or treat AD by decreasing amyloid plaque formation, clearing existing plaques, and chelating metal ions.89 Early studies with curcumin in AD did not provide evidence supporting its benefit in AD, but this may have been due to the poor oral availability of curcumin, insufficient dosing, and short duration of the trials. Synthetic formulations of curcumin as well as pharmaceutical modifications of the naturally occurring curcumin are being developed to improve the bioavailability of curcumin.91 Studies are ongoing to evaluate the efficacy, safety, and dosing of curcumin for the treatment of AD.
Medical Foods Several medical foods have been studied for the treatment of AD. Medical foods constitute a unique category that consists of ingestible entities specifically intended for the treatment of diseases that have “specific nutritional requirements” and in which the medical food may manipulate disease-relevant pathophysiology. Although medical foods regulatory approval standards are not as rigorous as those required for approvals of new medications, medical foods are obtained only by prescription. AC1202 (Axona®) is a mixture of medium-chain fatty acids, consisting primarily of the C8 fatty acid, caprylic acid. AC1202 is converted by the liver to a ketone body, β-hydroxybutyrate, which is released into the blood stream. β-Hydroxybutyrate crosses the blood–brain barrier and can be used as an oxidative phosphorylation substrate by neuronal mitochondria. Support for AC1202 efficacy in the treatment of AD comes mostly from a phase IIb trial in which subjects randomized to 40 mg per day of AC1202 for 45 days performed relatively better on the ADAS-cog than did subjects randomized to a placebo.103 A subanalysis of these data revealed that this benefit was entirely driven by subjects who did not have an APOE*4 allele. For APOE*4 carriers, ADAS-cog performance between subjects receiving AC1202 and placebo were comparable at all time points studied. GI-related side effects were common, but in general side effects were felt to be mild. Coconut oil is a source of caprylic acid, but does not contain sufficient quantities to meet the needs of a person with AD.90 Coconut oil continues to be used by some patients as a less expensive alternative to AC1202 however.
Souvenaid® with Fortasyn Connect™ is a medical food with clinical trial data supporting it use in AD but is not yet commercially available. This product is administered once daily and contains omega-3 fatty acids, phospholipids, choline, uridine monophosphate, vitamin E, vitamin C, selenium, vitamin B12, vitamin B6, and folic acid. The nutrients in this product are at levels above what could be obtained from a normal diet. It is believed that these ingredients provide precursors that increase phosphatides that, along with synaptic proteins, comprise synaptic membranes.90 In a randomized, double-blind, multicenter trial in treatment-naïve patients with mild to moderate AD receiving Souvenaid® with Fortasyn Connect™, improvement was seen after 12 weeks in one of two primary outcome measures of cognitive function.90 GI events were the most commonly reported adverse events. A second 24-week, randomized, controlled, double-blind, parallel-group, multicountry trial in treatment naïve patients with mild AD confirmed these findings.104
Clinical Controversy…
The use of medical foods in patients with AD remains controversial. Limited laboratory and clinical data are available on these products. Also, there is no postapproval safety monitoring required for products that are classified as medical foods. At this time there are no studies comparing the efficacy and safety of these products with other established cognitive-enhancing treatment options. Controversy exists between those who advocate for availability of dietary supplements to consumers and those who advocate for the exclusive application of evidence-based medicine. The major concern is the marketing of potentially ineffective products to those suffering from memory loss or dementia. Despite the lack of a clear evidence base, patient interest in these products continues. This may in part be driven by the limitations of currently available therapies for AD.
Tramiprosate Tramiprosate (homotaurine), or Alzhemed®, showed promise as a treatment for AD in early development. In animal studies, homotaurine demonstrated the ability to interfere with amyloid plaque formation and subsequent degeneration of neuronal cells. Phase III trials were disappointing, and the FDA declined to approve marketing of homotaurine as a prescription drug. Homotaurine is naturally occurring in seaweed, and is now available as the dietary supplement, Vivimind® for age-associated memory impairment.105
Omega-3 Fatty Acids Arguments that omega-3 fatty acids found in fish oil, such as docosahexaenoic acid and eicosapentaenoic acid, could benefit AD subjects have existed for some years. A large prospective, placebo-controlled trial of docosahexaenoic acid in AD subjects was recently reported. For the most part, results were disappointing, and although it could not be ruled out that population subsets did benefit, the primary study end points were negative.106 There is insufficient evidence at this time to recommend docosahexaenoic acid for the treatment of AD.
Drugs and Treatment Strategies in Development
New drug development is focused on disease modifying and prevention strategies and falls broadly into several categories: treatments designed to reduce levels of brain Aβ or manipulate its configuration, treatments targeting tau protein, antiinflammatory approaches, and therapies to address insulin resistance in the brain.
Reducing Aβ Formation To reduce brain amyloid levels, approaches to both reducing Aβ production and enhancing its removal have been and still are undergoing evaluation. Aβ is produced through enzymatic processing of APP by two enzyme complexes, the β- and γ-secretases. β-Secretase inhibitors have entered phase II and III human trials. Agents that specifically inhibit γ-secretase could prove problematic from a side-effect perspective, as γ-secretase is also critical for processing Notch3, a protein of developmental importance and perhaps brain maintenance. Certain NSAIDs (ibuprofen and flurbiprofen) influence γ-secretase, but do not inhibit it outright. In general, these NSAIDs alter where γ-secretase cuts the APP protein. An enantiomer of flurbiprofen, tarenflurbil, completed a large phase III efficacy trial in which no evidence of efficacy was seen.107 Stimulation of α-secretase blocks the formation of Aβand generates neuroprotective peptide that is another strategy to reduce Aβ. Therapies aimed at activating α-secretase are currently under investigation.107
Increasing Aβ Clearance Immunotherapy approaches have been studied as a way to enhance Aβ removal. The most extensive investigation involved AN1792, a Aβ-based vaccine. A phase II trial in humans was prematurely halted after a substantial percentage of those mounting a robust immune response to the vaccine experienced encephalitis, a potentially life-threatening brain inflammation. The most comprehensive, long-term clinicopathologic study of subjects receiving AN1792 later concluded that vaccinated subjects show a predictable rate of cognitive decline and that despite reducing brain plaque burdens, AN1792 vaccination is unlikely to meaningfully benefit those with the common form of late-onset, sporadic AD.108 Despite these failures, second-generation active immunization vaccines are undergoing Phase II trials that, hopefully, will not trigger encephalitis. Clinical development of two of the most promising Aβ monoclonal antibodies, bapineuzumab and solanezumab, was discontinued after disappointing results in Phase III clinical trials.109 The usefulness of treating AD subjects with IV immunoglobulin preparations, which naturally contain antibodies to Aβ, is under evaluation.107
Preventing Aβ Aggregation Proponents of the amyloid cascade hypothesis claim the species of Aβ that is most likely to prove relevant to AD neurodegeneration are Aβ oligomers formed through limited aggregation of Aβmonomers. Tramiprosate was designed to prevent Aβ oligomer formation and tested clinically in a large phase III trial. No evidence of efficacy was seen.107 Other agents targeted at this mechanism remain under clinical investigation. Metals such as zinc, copper, and iron play a role in Aβ aggregation. Metal chelators are also being developed for potential treatment of AD.107
Targeting Tau Targeting tau has been challenging, and thus far there are few therapeutic options in clinical trials. One approach is inhibition of kinase-mediated phosphorylation since tau hyperphosphorylation leads to tau dysfunction and aggregation. Agents under investigation include lithium and valproate.107 Protein phosphates are also being targeted to reduce hyperphosphorylation. Metformin and selenium are currently under investigation for this purpose. Tau aggregation inhibitors are also under study, including methylene blue.107
Reducing Oxidative Stress and Inflammation in the Brain Inflammation, oxidative stress, and mitochondrial dysfunction in chronic neurodegenerative disorders contribute to the neuronal dysfunction and loss that occurs in these conditions. Production of Aβ and hyperphosphorylated tau may simply be downstream cell responses to the cycle of inflammation and oxidative stress that eventually overwhelms the neuron’s ability to compensate. Targeting the upstream oxidative stress and inflammation is an active area of investigation. Nutriceuticals and vitamins, as well as antiinflammatory medications (etanercept, prednisone, ibuprofen, indomethacin, naproxen, celecoxib, rofecoxib, atorvastatin, simvastatin, rosuvastatin, pravastatin, rosiglitazone, and the mitochondrial stabilizer latrepirdine) have shown promising results in preclinical studies and early clinical investigations, but subsequent clinical trials have often been conflicting or negative.107 One possible explanation is that the benefit from these agents may be in primary prevention before damage is severe enough that symptoms of cognitive decline are evident.107
Targeting Insulin Resistance in the Brain Low levels of insulin and insulin resistance in the brain are associated with cognitive impairment and AD. Individuals with type 2 diabetes have a twofold higher risk of developing AD.110One of the actions of insulin in the brain is to modulate the levels of Aβ, leading researchers to explore this area for potential treatment opportunities. One promising approach is a new class of diabetes medications, glucagon-like peptide-1 receptor agonists. Liraglutide has been shown to reduce amyloid production and protect neurons from resulting damage in animal models.110 Early clinical studies with intranasal insulin showed improvement in memory and daily functioning in patients with MCI and mild or moderate AD.111 A large multicenter trial of this treatment strategy is scheduled to begin in 2013.110
Suggestions of efficacy in phase II trials in no way ensures efficacy will be seen in phase III trials. This caveat seems especially pertinent in AD drug development, as phase II trials of flurbiprofen, tramiprosate, rosiglitazone, latrepirdine, bapineuzumab, and solanezumab all reported some evidence of efficacy that did not bear out in phase III studies. Obviously, successful development of new AD treatments depends on elucidating AD’s true underlying pathophysiology. One reason for the failure of so many AD therapeutics may be that current strategies do not target the pathways that ultimately result in AD. Another reason may be that medications are being initiated when the disease has already progressed too far to be reversed.110 New approaches include studying amyloid-blocking agents in patients with genetic predisposition to young-onset AD before symptoms are present and studying patients with biomarkers of disease risk or presymptomatic signs of disease to determine the potential value of new treatments.109
Pharmacotherapy of Noncognitive Symptoms
Most patients with AD manifest noncognitive symptoms at some point in the illness.112 These symptoms can be roughly divided into three categories: psychotic symptoms, inappropriate or disruptive behavior, and depression. Effective management of these problems is important because behavioral symptoms are distressing to both the patient and the caregiver, necessitate increased caregiver supervision and patience, and are a leading reason for nursing home placement.
Strategies for treatment of psychotic or behavioral symptoms should include environmental interventions first, then pharmacologic interventions only when necessary. Behaviors such as agitation, aggression, delusions, hallucinations, repetitive vocalizations, and wandering may be caused by medications, medical illness (e.g., pain, constipation, dehydration, and infection), environmental precipitants, poor caregiving, physical/verbal abuse, and unmet physical or psychological needs. These possible underlying causes should be explored and corrected when possible before initiating drug therapies.25 The need for medications may exist when neuropsychiatric symptoms are of sufficient severity to cause significant distress to the patient or caregiver, interfere with function or cause disability, impede delivery of necessary care, or pose a danger to self or others.49,84,112 The balance between risks of the medication and expected benefits must be acceptable to the patient or surrogate decision maker. Medications should be used cautiously, with adequate monitoring for efficacy and adverse events.
Despite the high prevalence of noncognitive symptoms in AD, relatively little research has been conducted in these patients. Data from clinical trials of antidepressants, cholinesterase inhibitors, and antipsychotics are emerging, but more research is needed. To date, no drug has been approved by the U.S. FDA for the treatment of behavioral disturbances in patients with dementia. Because of limited clinical data, treatment is primarily empiric, with side-effect profiles used as a guide in selecting the appropriate treatment. Psychotropic medications with anticholinergic effects should be avoided because they may actually worsen cognition and interfere with cholinesterase inhibitor therapy.
General guidelines governing therapy can be summarized as follows: use reduced doses, monitor closely, titrate dosage slowly, and document carefully. Treatment should be considered as temporary.113Caregivers often have erroneous expectations regarding the effects of psychotropic medications, and the anticipated benefits and risks of therapy should be clearly explained. Disruptive behaviors and delusions wax and wane with disease progression. Attempts to slowly taper and discontinue medication should be undertaken regularly in minimally symptomatic patients, because some patients improve on medication withdrawal.84 Table 38-8 outlines suggested doses of medications.
TABLE 38-8 Medications Used for Noncognitive Symptoms of Dementia
Cholinesterase Inhibitors and Memantine
Clinical trials with cholinesterase inhibitors have consistently reported modest benefit in managing neuropsychiatric symptoms, although these are generally not the primary outcomes studied in the trials.114–117 Any benefits in symptoms such as agitation may accrue gradually over time, since cholinesterase inhibitors may not significantly reduce agitation when administered to patients experiencing acute agitation.118 Memantine shows modest behavioral benefits as well, either alone or in combination with cholinesterase inhibitors, and may also spare the use of antipsychotics to treat agitation.114,115,117 These treatments can provide modest short-term improvement and possibly slow the development and progression of behavioral symptoms. Cholinesterase inhibitors also have a small beneficial effect on caregiver burden and active time use among caregivers of persons with AD.119 These benefits should be considered along with cognitive benefits in treatment decisions. Long-term effects on behavior have not been demonstrated to date, and further research is needed.
Antipsychotics
Antipsychotics are widely used in the management of neuropsychiatric symptoms in AD. There is modestly convincing evidence that most of the atypical antipsychotics provide some benefit for particular neuropsychiatric symptoms, but these data have been insufficient to gain FDA approval as an indication for the management of behavioral symptoms in AD. Based on a meta-analysis, only 17% to 18% of dementia patients show a treatment response to atypical antipsychotics.120 In a double-blind, placebo-controlled trial of 421 outpatients with AD and psychosis, aggression, or agitation randomized to receive olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks, there were no significant differences among the treatments in time to discontinuation of treatment or improvement in the Clinical Global Impression of Change scale. The investigators concluded that adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for treatment of psychosis, aggression, or agitation in patients with AD.120 A recent systematic review and meta-analysis found small but statistically significant benefits in global behavioral symptom scores in elderly patients with dementia for aripiprazole, olanzapine, and risperidone.121 Adverse events are common with atypical and typical antipsychotics in patients with AD. These adverse events associated with atypical antipsychotics include somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death.122 These findings resulted in a FDA-mandated “black box warning” concerning the use of atypical antipsychotics in the treatment of AD. Typical antipsychotics may also be associated with a small increased risk of death, as well as more severe extrapyramidal effects and hypotension. Chapter 50 includes a more detailed discussion of antipsychotic adverse events. Overall, there is a modest expectation of treatment benefit and potential for significant harm associated with antipsychotic use in patients with AD. Individual risk and benefit must be considered when initiating therapy. Prescribing of antipsychotics in AD should be restricted to patients with severe symptoms that have not responded to other measures and treatment should rarely be continued beyond 12 weeks.123 Diligent monitoring during treatment is essential along with frequent reassessment of continued need.
Antidepressants
Depressive symptoms are common in patients with AD. Apathy is seen in 48% to 92% of individuals with dementia, and clinically significant depression occurs in approximately 32% with mild dementia, 23% with moderate disease, and 18% in the severe stage of the dementia.117 Some trials have studied the efficacy of antidepressants in treating depression in patients with AD, but the results are conflicting.124Small sample size, short duration of treatment, and differing measures of therapy outcomes limit comparison across studies and may account in part for conflicting study results.117 Improvement in patients receiving placebo is also common. In practice, treatment with selective serotonin reuptake inhibitors (SSRIs) is initiated most commonly in patients with AD, based on side-effect profile and evidence of efficacy,49,125 however a recent study comparing sertraline, mirtazapine, and placebo found no benefit for these agents in treating depression in patients with dementia.126 Among the SSRIs, the best evidence exists for sertraline and citalopram.115 Serotonergic function may also play a role in some of the other behavioral symptoms of AD, and some studies support the use of SSRIs in the management of these behaviors, even in the absence of depression.115 Tricyclic antidepressants have efficacy similar to the SSRIs, but should generally be avoided because of their anticholinergic activity.49 There is little evidence for the use of trazodone to manage behavioral or depressive symptoms, but it is commonly recommended to treat insomnia in patients with AD.49
Chapter 51 has a more complete discussion of treatment of depression.
Miscellaneous Therapies
Because antipsychotic and antidepressant therapy has shown only modest efficacy and poses a risk of undesirable side effects, medications traditionally used to treat disruptive behaviors and aggression in other psychiatric and neurologic disorders have been suggested as potential alternatives. These alternatives include benzodiazepines and antiepileptics.117,123
Benzodiazepines have been used to treat anxiety, agitation, and aggression, but the benefit is generally modest.49 There are no RCTs that have investigated the use of benzodiazepines for the management of behavioral disturbances in AD. Because benzodiazepines impair cognition, worsen breathing disorders, and may increase the risk of falls in AD patients, their routine use is not advised, except on an “as needed basis” for infrequent episodes of agitation.49,117 “Mood stabilizer” anticonvulsants such as carbamazepine, valproic acid, or gabapentin may be appropriate alternatives, but evidence is conflicting.115,117 Clearly, more rigorous placebo-controlled studies are needed to determine the relative efficacy and place in therapy for these medication alternatives.
Noncognitive symptoms are often the most difficult aspect of AD for the caregiver. When nonpharmacologic approaches fail, selected antipsychotics and antidepressants have been useful for effective management of behavioral, psychotic, and depressive symptoms, thereby easing caregiver burden and allowing the patient to spend additional time at home. Alternative treatments are available when initial choices are not successful. Adverse events remain an important concern in this population.
Clinical Controversy…
The appropriate use of medications in the management of behavioral disturbances in patients with dementia continues to be controversial. Nonpharmacologic approaches are considered first-line therapy, but evidence for individual nonpharmacologic strategies is often lacking, and there are many barriers to implementing these approaches consistently. Nonpharmacologic strategies require caregiver education and training, sufficient staffing resources in facilities or caregiver time at home, and availability of necessary supplies or equipment. Overcoming these barriers is challenging, but an important step in minimizing the use of medications for managing behavioral disturbances in AD.
PERSONALIZED THERAPY
At this time there are no specific recommendations regarding the choice of agent or dosing regimen for current cognitive enhancing therapies based on genotype or other biomarkers. There is a great deal of attention among AD researchers to identify biomarkers for AD, and recommendations are likely to evolve over time as we better understand the underlying pathophysiology of AD and the predictors of patient response. Recommendations for patients with renal or hepatic dysfunction or low body weight are detailed in Table 38-6. It is important to consider that most patients with AD are older adults and therefore may be taking multiple medications for other acute and chronic health conditions. The potential for adverse events due to drug interactions increases as the number of medications increases.
EVALUATION OF THERAPEUTIC OUTCOMES
An evaluation of therapeutic outcomes in the patient with AD begins with a thorough assessment at baseline and a clear definition of therapeutic goals. Cognitive status, physical status, functional performance, mood, and behavior all need to be evaluated before initiation of drug therapy. The clinician should interview both the patient and the caregiver to assess response to drug therapy. In evaluating response to cognitive agents, the clinician should ask questions about the patient’s ability to perform daily functional tasks and about mood and behavior, as well as questions about memory and orientation. Objective assessments such as MMSE for cognition assessment, the Physical Self-Maintenance Scale for assessment of activities of daily living, and the Neuropsychiatric Inventory Questionnaire for assessment of behavioral disturbances can be used to quantify changes in symptoms and function.127
Because target symptoms of psychiatric disorders may respond differently in dementia patients, a detailed list of symptoms to be treated should be documented in the pharmacotherapy plan to aid in monitoring. These could include, for example, “striking at spouse because patient believes spouse is an impostor,” “verbal threats and refusal to allow clothes to be changed,” and so on, as opposed to documenting vague symptoms such as “aggression” or “delusions.” To make an accurate assessment of depression, multiple symptoms (e.g., sleep, appetite, and activity and interest levels) need to be assessed in addition to the patient’s stated mood.
The patient should be observed carefully for potential side effects of drug therapy. The specific side effects to be monitored and the method and frequency of monitoring should be documented. Patients should be monitored for therapeutic effect 8 weeks after initiation of therapy and least every 6 months thereafter.127 However, patients need to be treated for an adequate duration to see a therapeutic effect from a given intervention. Because the effects of cognition-enhancing medications are not great, a treatment period of several months to a year may be necessary before it can be determined whether therapy is beneficial. Cognitive effects of the drug are often noticed only as a plateauing during treatment or as deterioration following drug discontinuation. In general, cognitive agents should be continued if the patient is demonstrating no change in clinical status. However, if there is doubt, the medication can be slowly tapered and discontinued, and the patient monitored off the drug for 4 to 6 weeks to determine the need for continued therapy.
ABBREVIATIONS
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